The liver is central to mammalian metabolism and plays a critical role in providing fuel to other tissues particularly when food is limiting. People with disparate inborn errors in mitochondrial fatty acid ?-oxidation exhibit life-threatening hypoketotic-hypoglycemia following a fast due to the critical role of fatty acid oxidation to gluconeogenesis and ketogenesis. To understand the contribution of hepatic fatty acid oxidation to systemic metabolic dysfunction, we have generated mice that cannot oxidize long chain fatty acids via mitochondrial ?-oxidation specifically in hepatocytes by the conditional deletion of Carnitine Palmitoyltransferase 2 (Cpt2), an obligate step encoded by a single gene. Here we will leverage this model to understand the contribution of fatty acid oxidation to hepatic and extrahepatic regulation of systemic metabolic homeostasis during fasting and high fat dietary challenges. Herein we propose three specific aims. 1. Determine the requirements of hepatic fatty acid oxidation during fasting. 2. Determine the role of hepatic fatty acid oxidation in high fat diet- induced body weight and glucose tolerance. 3. Determine the mechanism of fatty acid-induced transcription. The long-term goal is to understand the roles and requirements of hepatic lipid metabolism during fasting and high fat feeding. The expectation is that our proposed studies will describe the requirements of hepatic fatty acid oxidation in fasting and the development of obesity and glucose intolerance. Additionally, we will uncover new rolls for hepatokines and metabolic signaling in the control of systemic metabolic physiology.